Project Summary/Abstract Heart Failure with a Preserved Ejection Fraction (HFpEF) has proved notoriously resistant to therapies that are standard for heart failure with a reduced ejection fraction (HFrEF). The dominant symptom in patients with HFpEF is dyspnea on exertion (DOE), resulting in limited exercise tolerance that is as severe as patients with HFrEF. However the mechanisms leading to DOE and impaired exercise tolerance are surprisingly unclear. One universal finding is an elevated pulmonary capillary wedge pressure (PCW) during exercise, even in those patients with a normal PCW at rest. However it is not clear whether this rise in filling pressure is the cause of symptoms leading to exercise cessation, or rather a secondary finding which is associated with, but not causative of dyspnea and exercise intolerance. The only way to test this hypothesis for certain is to lower cardiac filling pressure acutely, and see if exercise capacity increases, along with increased oxygen extraction and HR. The global objective of this project therefore is to directly test the ?central mechanism? of exercise intolerance in HFpEF. Hypothesis 1/ Specific Aim 1: To test the hypothesis that patients with HFpEF have DOE and impaired functional capacity due to an excessive rise in PCW during exercise, we will directly measure PCW, as well as comprehensive invasive and non-invasive cardiovascular hemodynamics during sustained upright submaximal and maximal exercise, before and after lowering of filling pressure with organic nitrates (nitroglycerin). Lung ultrasound will be used to identify ?comet tails?, along with acute changes in thoracic impedance to assess for development of subclinical pulmonary edema. Hypothesis 2/Specific Aim 2: We hypothesize that patients with HFpEF who have a ?central phenotype? (lowering filling pressure increases exercise capacity with an increase in HR and a-v O2 difference) will respond best to exercise training facilitated by the acute lowering of filing pressure during each training session to a greater degree than a training program focused on improving skeletal muscle metabolism alone (small muscle mass exercise). We will randomly assign HFpEF patients with both a ?central phenotype? and a ?peripheral phenotype? (no change in exercise capacity or persistently low a-v O2 diff with lowering of PCW) to either a centrally based exercise intervention (acute lowering of PCW with TNG during each training session) or a peripherally based exercise intervention (single leg kicking exercise). Patients will undergo 16 weeks of training including endurance and high intensity intervals, after which all baseline measures will be repeated. This project will be greatly enhanced by the tightly integrated link with projects 2-4 plus the imaging core in which comprehensive assessment of skeletal muscle oxygen utilization, autonomic function, and pulmonary limitations to exercise will be quantified along with high resolution assessment of dyspnea. After these aims are accomplished, we will have achieved the most comprehensive assessment of exercise intolerance and mechanisms of DOE ever performed in HFpEF, which will allow detailed, ?precision? phenotyping of this complex and multifactorial disease. We also will have tested specific, creative strategies for improving exercise tolerance in such patients.